In spite of extensive efforts conducted for decades all over the world, cancer still remains one of the most incurable diseases. Recently, with great and brilliant advances in all sorts of sciences comprising cancer biology and medicinal chemistry, anticancer agents such as Gleevec®, which have innovative mechanisms, have been developed. Since the completion of the Human Genome Project, new molecules that are targets of anticancer agents have been discovered.
HIF-1 (Hypoxia Inducible Factor-1) is a heterodimeric transcription factor composed of two subunits: HIF-1α subunit, an oxygen-dependent decomposition domain; and HIF-1β subunit, a constitutively expressed domain [Cancer Metastasis Rev. 17, 187-195, 1998; Trends Mol. Med. 7, 345-350, 2001]. Under normal oxygen concentrations, the HIF-1α protein is hydroxylated depending on the oxygen at proline residues 402 and 564, thereby it will be ubiquitinated by interacting the tumor suppressor pVHL (von Hippel-Lindau) and decomposed by proteasome. In hypoxia, however, these consecutive reactions are inhibited, so that the HIF-1α protein is accumulated and translocated as a dimeric complex associated with the preexisting HIF-1β protein into the nucleus [Science 292, 468-472, 2001]. HIF-1β expression is relatively constant, therefore HIF-1 action depends on the stability and expression regulation of HIF-1α mainly. The stability of HIF-1α depends not only on partial oxygen pressure but also on factors involved in an oxygen sensing pathway, including transition metal ions, iron chelators, and antioxidants. In addition, the HIF-1α protein can accumulate irrespective of oxygen concentrations by activation of growth factors, such as epidermal growth factor, heregulin, insulin-like growth factor-I, insulin-like growth factor-II, etc., or of oncogenes, such as Her2 oncogene (Human Epidermal Growth Factor Receptor 2), etc. When these growth factors bind to respective receptors, HIF-1α protein is synthesized by activating the PI3K-AKT or MAPK signal transduction pathway, with the result that the HIF-1α protein accumulates.
Within a nucleus, HIF-1α/HIF-1β is associated with an HRE (Hypoxia Responsive Element, 5′-ACGTG-3′) on the promoter of a target gene to induce the expression of the gene. There are about 60 genes that have been known to be regulated by HIF-1, including a vascular endothelial growth factor (VEGF) gene [Nat. Rev. Cancer 2, 38-47, 2002; J. Biol. Chem. 278, 19575-19578, 2003; Nat, Med. 9, 677-684, 2003; Biochem. Pharmacol. 64, 993-998, 2002].
Hypoxia is usual in cancer, in particular solid cancer. Because solid cancer cells are adapted to a low oxygen condition after being subjected to various genetic alterations, they become more malignant and resistant to anticancer agents. In fact, hypoxia is known to play an important role in malignant cancer in over 70% of all cancer types [Nature 386, 403, 1997; Oncol. 28, 36-41, 2001, Nat. Med. 6, 1335, 2000; Cancer 97, 1573-1581, 2003].
HIF-1 is one of the most important molecules regulating the adaptation of cancer cells to hypoxia, and the amount of HIF-1α protein is closely correlated with poor prognosis of cancer patients. Whether attributed to the hypoxia, or above-mentioned the stimulation of growth factors or the activation of oncogenes, or the inactivation of tumor suppressors, such as pVHL, the cancer cells are activated, HIF-1α induces the expression of various genes encoding, for example, hexokinase 2, glucose transporter 1, erythropoietin, IGF-2, endoglin, VEGF, MMP-2, uPAR, MDR1, etc., leading to improvement in apoptosis resistance, angiogenesis, cell proliferation, and invasiveness, thereby resulting in the malignant transformation of cancer cells.
In addition, it is known that HIF-1 overexpression increased patient mortality through tumor growth stimulation and resistance to chemotherapy and radiation. Because it plays a pivotal role in the growth, proliferation and malignant transformation of cancer, in particular, solid cancer, HIF-1 has become a major target of many anticancer agents, and active and extensive research has been conducted thereon [Cancer Res. 62, 4316, 2002; Nat. Rev. Drug Discov. 2, 1, 2003; Nat. Rev. Cancer 3, 721-732, 2003].
Recently, a significant number of preexisting anticancer agents, such as taxol, rafamycin and 17-AAG (17-allylaminogeldanamycin), or small molecular compound YC-1(3-(5′-hydroxymethyl-2′-furyl)-1-benzylindazole) are undergoing various clinical demonstrations for use as HIF-1α inhibitors [Nat. Rev. Drug Discov. 2, 1-9, 2003; Nat. Rev. Cancer 3, 721-732, 2003; JNCI 95, 516, 2003], and cell based reporter assays for screening HIF-1α inhibitors of new structures are being actively conducted by taking advantage of HRE [Cancer Res. 65, 4918, 2005; Cancer Cell 6, 33, 2004; Cancer Res. 62, 4316, 2002]. However, these are in the early stage of drug discovery.
HIF-1α can be used as a valid target for novel anticancer therapeutics. Angiogenesis factors which are derived by an activated HIF-1α in hypoxia condition, such as VEGF, are associated with the progress of diabetic retinopathy and rheumatoid arthritis as well as cancer.
In addition, the compounds that inhibit an activated HIF-1α from hypoxia condition can also be used as novel therapeutics for the diseases comprising diabetic retinopathy and rheumatoid arthritis [Pathol. Int. 55, 603-610, 2005].
Consequently, the present inventors have prepared compounds that inhibit the HIF-1α activity and angiogenesis excellently, and have high safety in vivo. Therefore, HIF-1α inhibitors, treating the disease comprising diabetic retinopathy and rheumatoid arthritis which are derived by an activated HIF-1α, are developed.